rs2229265

Variant names:

• chr2-169176479-C-T
• rs2229265
• NM_004525.3:c.10503G>A
• LRP2 p.Gln3501Gln

Your query was ambiguous. Multiple possible variants found:

• chr2-169176479-C-T
• chr2-169176479-C-G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004525.3(LRP2):​c.10503G>A​(p.Gln3501Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.498 in 1,613,744 control chromosomes in the GnomAD database, including 206,212 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.45 (16472 hom., cov: 32)
  • Exomes 𝑓: 0.50 (189740 hom.)
• Consequence: LRP2 NM_004525.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -1.74
• Publications: 16 publications found

Genes affected

LRP2 (HGNC:6694): (LDL receptor related protein 2) The protein encoded by this gene, low density lipoprotein-related protein 2 (LRP2) or megalin, is a multi-ligand endocytic receptor that is expressed in many different tissues but primarily in absorptive epithilial tissues such as the kidney. This glycoprotein has a large amino-terminal extracellular domain, a single transmembrane domain, and a short carboxy-terminal cytoplasmic tail. The extracellular ligand-binding-domains bind diverse macromolecules including albumin, apolipoproteins B and E, and lipoprotein lipase. The LRP2 protein is critical for the reuptake of numerous ligands, including lipoproteins, sterols, vitamin-binding proteins, and hormones. This protein also has a role in cell-signaling; extracellular ligands include parathyroid horomones and the morphogen sonic hedgehog while cytosolic ligands include MAP kinase scaffold proteins and JNK interacting proteins. Recycling of this membrane receptor is regulated by phosphorylation of its cytoplasmic domain. Mutations in this gene cause Donnai-Barrow syndrome (DBS) and facio-oculoacoustico-renal syndrome (FOAR).[provided by RefSeq, Aug 2009]

LRP2 Gene-Disease associations (from GenCC):

• Donnai-Barrow syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet
• Stickler syndrome

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• intellectual disability

  Inheritance: AD Classification: LIMITED Submitted by: G2P
• congenital heart disease

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 2-169176479-C-T is Benign according to our data. Variant chr2-169176479-C-T is described in ClinVar as Benign. ClinVar VariationId is 129490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.74 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.592 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004525.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP2	NM_004525.3	MANE Select	c.10503G>A	p.Gln3501Gln	synonymous	Exon 54 of 79	NP_004516.2	P98164

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRP2	ENST00000649046.1	MANE Select	c.10503G>A	p.Gln3501Gln	synonymous	Exon 54 of 79	ENSP00000496870.1	P98164
	LRP2	ENST00000649153.1		n.1401G>A		non_coding_transcript_exon	Exon 6 of 30	ENSP00000497617.1	A0A3B3IT64

Frequencies

GnomAD3 genomes AF: 0.451 AC: 68471 AN: 151888 Hom.: 16459 Cov.: 32

Gnomad AFR AF: 0.320

Gnomad AMI AF: 0.448

Gnomad AMR AF: 0.602

Gnomad ASJ AF: 0.452

Gnomad EAS AF: 0.104

Gnomad SAS AF: 0.479

Gnomad FIN AF: 0.454

Gnomad MID AF: 0.491

Gnomad NFE AF: 0.519

Gnomad OTH AF: 0.467

GnomAD2 exomes AF: 0.482 AC: 121013 AN: 251286 AF XY: 0.482

Gnomad AFR exome AF: 0.320

Gnomad AMR exome AF: 0.666

Gnomad ASJ exome AF: 0.459

Gnomad EAS exome AF: 0.0978

Gnomad FIN exome AF: 0.455

Gnomad NFE exome AF: 0.515

Gnomad OTH exome AF: 0.499

GnomAD4 exome AF: 0.503 AC: 734999 AN: 1461738 Hom.: 189740 Cov.: 53 AF XY: 0.502 AC XY: 365166 AN XY: 727174

African (AFR) AF: 0.312 AC: 10446 AN: 33480

American (AMR) AF: 0.658 AC: 29444 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.457 AC: 11932 AN: 26134

East Asian (EAS) AF: 0.114 AC: 4508 AN: 39696

South Asian (SAS) AF: 0.490 AC: 42291 AN: 86256

European-Finnish (FIN) AF: 0.454 AC: 24242 AN: 53414

Middle Eastern (MID) AF: 0.501 AC: 2890 AN: 5768

European-Non Finnish (NFE) AF: 0.522 AC: 580537 AN: 1111884

Other (OTH) AF: 0.475 AC: 28709 AN: 60390

GnomAD4 genome AF: 0.451 AC: 68522 AN: 152006 Hom.: 16472 Cov.: 32 AF XY: 0.450 AC XY: 33439 AN XY: 74296

African (AFR) AF: 0.320 AC: 13271 AN: 41432

American (AMR) AF: 0.602 AC: 9212 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.452 AC: 1568 AN: 3470

East Asian (EAS) AF: 0.104 AC: 535 AN: 5168

South Asian (SAS) AF: 0.480 AC: 2312 AN: 4816

European-Finnish (FIN) AF: 0.454 AC: 4791 AN: 10548

Middle Eastern (MID) AF: 0.500 AC: 147 AN: 294

European-Non Finnish (NFE) AF: 0.519 AC: 35293 AN: 67966

Other (OTH) AF: 0.467 AC: 987 AN: 2112

Alfa AF: 0.481 Hom.: 35473

Bravo AF: 0.454

Asia WGS AF: 0.346 AC: 1203 AN: 3478

EpiCase AF: 0.520

EpiControl AF: 0.529

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	not provided (3)
-	-	2	Donnai-Barrow syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.032
DANN	Benign	0.18
PhyloP100		-1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2229265;

hg19: chr2-170032989;

COSMIC: COSV55546414;

COSMIC: COSV55546414;